Autoantibodies to beta-amyloid are common in the ageing population
and in Alzheimer’s disease and may derive from aberrant forms of beta-amyloid
(Abeta) or from antigens with homology to it. The latter seems likely, as
glycoprotein B of the Herpes simplex virus (HSV-1) and 69 other viruses and
phages, including HHV-6, Hepatitis C, polyoma viruses and HIV-1 show exact
homology with a VGGVV C-terminal fibrillogenic sequence, an epitope that labels
beta-amyloid in the Alzheimer’s disease brain. Other viruses, including those
causing the common cold and influenza also show significant homology with
known and predicted beta amyloid epitopes, as do a number of allergens (food,
pollen and insect venoms and most notably house dust mites). Bacteria implicated
as risk factors in Alzheimer’s disease (C.Pneumoniae, B.Burgdorferri , H.Pylori,
P.Gingivalis) also contain matching Abeta proteins as does the meningitis
causing fungus, C.Neoformans, which has been associated with a rare but curable
misdiagnosed form of Alzheimer’s disease. Immune activation occurs in the
Alzheimer’s disease brain, as evidenced by many immune-related proteins in
plaques and by the presence of the complement membrane attack complex in neurones.
These observations suggest that Alzheimer’s disease is an autoimmune disorder
triggered by pathogens with homology to beta-amyloid, whose antibodies target
and kill the neurones within which the peptide resides, via immune and inflammatory
activation and complement-related lysis. Viruses matching the Abeta target
regions of beneficial catalytic autoantibodies include those from components
of the Mediterranean diet (plant viruses) and from the papillomavirus and
other cancer-inducing viruses, both of which (cancer and diet) are inversely
associated with Alzheimer’s disease risk. As a vaccine against the human papillomavirus
already exists, it may have a role to play in the prevention of Alzheimer’s
disease. This scenario explains most of the epidemiological observations in
Alzheimer’s disease which is more common in women and Afro-Americans, as is
HSV-2 seroprevalence; related to the number of pregnancies and thus greater
exposure to childhood infections, and less severe in nuns, who are shielded
from sexually transmitted diseases. Atopy and autoimmune disorders are common
in Alzheimer’s disease in accord with allergen homology to Abeta, and the
use of anti-inflammatory agents has been reported to reduce the risk of developing
Alzheimer’s disease. HIV-1 infection can cause dementia with Alzheimer’s disease
pathology, again in accord with Abeta homology. The four major risk genes
in Alzheimer’s disease, APOE, clusterin, complement receptor 1 and PICALM
can all be related to viral life cycles and clusterin and complement receptor
1 are both complement inhibitors. This scenario is also relevant to familial
Alzheimer’s disease, as the four mutant forms of APP717 and the
Swedish mutant (APP670/671) convert the surrounding peptide to
matches with commensal bacterial flora (E.Coli, E. Faecalis, P.Gingivalis)
and to viruses with high seroprevalence (HHV-6, norovirus and polyoma viruses)
and to those causing influenza and the common cold. Multiple lines of evidence
thus suggest that late-onset and Familial Alzheimer’s disease are autoimmune
disorders caused by diverse common pathogens and allergens that are homologous
to beta-amyloid or mutant APP fragments. Antibodies to these multiple agents
are a likely source of the autoantibodies to beta-amyloid in the ageing population
and would accumulate with repeated antigen exposure and age, the greatest
risk factor in Alzheimer’s disease. Vaccination, which has already been shown
to reduce the incidence of Alzheimer’s disease (diphtheria, influenza, tetanus,
and polio), pathogen screening and elimination, and immunosuppressant therapy
may be of therapeutic benefit in this disorder. This scenario is also relevant
to several other autoimmune disorders including multiple sclerosis, myasthenia
gravis, pemphigus vulgaris, systemic lupus erythematosus, and Chronic obstructive
pulmonary disease where the known autoantigens also line up with the reported
viral risk factors. Mutant proteins from other genetic diseases (Huntington’s
disease and other PolyGlutamine repeat disorders) and cystic fibrosis also
align with very common viruses. This may well be a near universal phenomenon,
reflecting the idea that all life evolved from viruses, which have however
left behind a deadly legacy of human viral derived proteins with homology
to antigenic regions of the current virome. This could well be responsible
for most of our ills. This also suggests that vaccination using epitopes to
the non-homologous regions of the viral culprits may be of benefit in autoimmune
and even in human genetic disorders.

Introduction

Autoantibodies to beta-amyloid are common in the ageing population
and in Alzheimer’s disease and may exert a beneficial role in adsorbing the
toxic peptide or catalysing its destruction. They may also mount an immune
attack against beta-amyloid, activating inflammatory pathways and complement
cascades that kill the neurones in which the peptide resides (1-3) . The membrane
attack complex of the complement pathway is present in Alzheimer’s disease
neurones (4;5) , supporting a role for aberrant immune/complement activation
within the brain. The source of these autoantibodies is not clear. They could
be derived as a response to abnormal forms of beta-amyloid or from antibodies
to other antigens that cross-react with the peptide.

It has already been noted that glycoprotein B of the Herpes simplex
virus shows marked homology with beta-amyloid, particularly matching a VGGVV
C-terminus pentapeptide (6) (Fig 1). The VGGVG epitope has been used to label
beta-amyloid1-40 in extracellular neurofibrillary tangles (7) .
This pentapeptide, per se, forms aggregates characterised by twisted
ropes and banded fibrils (8) . This is a characteristic of both beta-amyloid
and of HSV-1 glycoprotein B peptide fragments containing this sequence. The
viral glycoprotein B fragments form thioflavine T positive fibrils which accelerate
beta-amyloid fibril formation, and are neurotoxic in cell culture (9) .Herpes
simplex infection (HSV-1) has been shown to be a risk factor in Alzheimer’s
disease, acting in synergy with possession of the APOE4 allele (10) . HSV-1
infection in mice or neuroblastoma cells increases beta-amyloid deposition
and phosphorylation of the microtubule protein tau (11;12) .Viral infection
in mice also results in hippocampal and entorhinal cortex neuronal degeneration
and memory loss, all as found in Alzheimer’s disease (13) . A recent study
has also shown that anti-HSV-1 immunoglobulin M seropositivity, a marker of
primary viral infection or reactivation, in a cohort of healthy patients,
was significantly associated with the subsequent development of Alzheimer’s
disease. Anti-HSV-1 IgG, a marker of lifelong infection showed no association
with subsequent Alzheimer’s disease development (14) . All of these factors
support a viral influence on the development of Alzheimer’s disease. Antibodies
to the Potato virus Y, which is highly homologous to beta-amyloid (Fig 1),
are also able to label beta-amyloid containing plaques in the Alzheimer’s
disease brain (15) . It is therefore possible that beta-amyloid autoantibodies
are derived from such homologous antigens. Homology searches within viral
and microbial proteomes and allergenic proteins showed that many are highly
homologous to immunogenic regions of the beta-amyloid peptide and also that
APP mutations in Familial Alzheimer’s disease convert the surrounding peptides
to matches to very common viruses and bacteria.

Methods

Homology searches against viral, bacterial or fungal proteomes
were performed via the NCBI or Uniprot BLAST servers and sequence alignments
via the CLUSTAL server at UniProt (16) . Homology with allergen sequences
was determined by interrogation of the Structural database of Allergenic Proteins
(17) http://fermi.utmb.edu/SDAP/index.html
and from homology searches at the AllergenOnLine database http://www.allergenonline.org/ (18)
. Epitopes containing viral/beta amyloid matching sequences were found using
the Human Immune epitope database. www.immuneepitope.org
(19) . B-Cell epitopes were identified using the BepiPred server http://www.cbs.dtu.dk/services/BepiPred/
(20) .

Results

The homology between HSV-1 glycoprotein B and beta-amyloid1-42
is shown in Fig 1. A homology search against viral proteomes showed
that a number of other viruses contain this VGGVV sequence (Table 1). These
include adenovirus 8, Dengue virus, Herpes Simplex (HSV-1, 2 and 6) hepatitis
C, Lactate dehydrogenase-elevating virus, the polyoma virus and HIV-1, viruses
infecting family pets (cats, guinea pigs and goldfish) and farmyard animals
(cattle, horses, pigs and poultry) and viruses infecting certain foodstuffs
(cherries, radish, strawberries and raspberries, tomatoes, potatoes, watermelon,
oysters, salmon and shrimp). The VVGGV sequence is also present in a number
of phages infecting bacteria that cause common childhood and adult diseases
(Gastroenteritis, food poisoning, hospital infections (nococosmial), and wound
infections). It should be noted that the VGGVV sequence was restricted to
69 viruses and phages (Table 1) out of 2463 viral genomes in the NCBI database.

A further homology search against the viral proteome
database revealed that many other common viruses express proteins with marked
homology (pentapeptides or more) to other sequences within the beta-amyloid
peptide (Table 2). These viruses include Adenovirus D, Coxsackie virus B2,
influenza, hepatitis C and Yellow fever, numerous HIV-1 or HIV-2 proteins,
and the human papillomavirus. Bovine and poultry viruses were also well represented.
Phages infecting campylobacter, enterobacteria, lactococcus, mycobacterium,
streptococci and vibrio (Pentapeptide or more) as well as Listeria and pseudomonas
(Tetrapeptide matches) were also represented . These infect very common benign
or infection-related bacteria. Although less homologous, viruses causing the
common cold, mumps, rubella and polio nevertheless contained exactly matching
tetrapeptide beta-amyloid sequences.

Numerous plant viruses contain both the VGGVV
and other matching beta-amyloid sequences. Plant viruses are generally considered
as benign or unable to infect humans. However, they are obviously ingested
and exist in human faeces (21) . The Pepper mottle virus has recently been
associated with fever in Man (22) suggesting that phytonosis might be more
common than thought. A capsid protein of this virus contains the YEVHHQ sequence
of beta-amyloid as do a number of other plant viruses, including the potato
virus. This sequence is immunogenic (in beta-amyloid) and antibodies to the
potato virus label amyloid plaques in the Alzheimer’s disease brain (15) .
Sequences within the potato virus polyprotein show 54% identity with beta-amyloid1-28
(Fig 1).

Many of the viruses containing beta-amyloid sequences
are very common (eg influenza and Herpes viruses and even the common cold
virus) and the beta-amyloid matching phages are associated with a number of
bacteria causing common gastrointestinal problems (e.g. clostridum, salmonella
and vibrio) or associated with hospital infections (Pseudomonas, Serratia).
Exposure to these agents, which possess myriad strains, is ineluctable and
each exposure is likely to increase the risk of generating antibodies that
might also target the beta-amyloid peptide.

Bacteria and Fungi implicated in Alzheimer’s disease

The VGGVV sequence, and others, are also present in proteins
from C.Pneumoniae, Borrelia Burgdorferri and Helicobacter pylori (Table 3)
all of which have been implicated as risk factors in Alzheimer’s disease (23;24)
. Indeed, in infected Alzheimer’s disease patients, H.Pylori eradication can
have beneficial effects on cognition (25) . C.Pneomoniae (penta- and hexapeptides)
B.Burgdorferri (pentapeptides) and H.Pylori (Penta- and hexapeptides) proteins
all contain matching beta-amyloid fragments. Tooth loss and periodontitis
have also been cited as risk factors in Alzheimer’s disease (26;27) . Porphyromonas
gingivalis and Streptococcus mutans are major cause of periodontitis, and
proteins from these bacteria also contain the VGGVV and other internal beta-amyloid
sequences (Table 3).

There are two case reports in the literature recording
subjects diagnosed with Alzheimer’s disease, both with a three year history
of dementia. Cryptococcal meningitis was subsequently diagnosed, and in both
cases, antifungal treatment resulted in an almost complete recovery (28;29)
C.Neoformans is the agent responsible for Cryptococcal meningitis and contains
a number of proteins showing a striking similarity with beta-amyloid internal
sequences, including exact homology with an N-terminus octapeptide and a c-terminus
heptapeptide as well as the VGGVV sequence (Table 3).

Allergenic proteins

A search of the allergen databases showed that stretches within the beta-amyloid
peptide, exactly match those in several common allergens, particularly in
European (hexapeptide) and American (pentapeptide) house dust mites (Table
2, Fig 3 ) and in a rice fungus Aspergillus Oryzae. Rather less pentapeptide
or more matches were found in this class but very many common pollen, fungal
, insect venom, domestic animal (cat, cattle and horse) and food allergens
(beans, rice, potato, tomato and nuts ) contain tetrapeptide sequences matching
those of beta amyloid . House dust mites, as well as containing relatively
large consensual sequences, display a large number of smaller peptide matches
along the length of the beta-amyloid peptide (Table 2) suggesting that these
ubiquitous and unavoidable creatures could play a rather unexpected role in
Alzheimer’s disease.

Immune activation in the Alzheimer’s disease brain

A number of immune-system related proteins are found in amyloid
plaques or neurofibrillary tangles. Interleukin 1 alpha, interleukin 6, and
tumor necrosis factor are all been localised within plaques (30) and acute
phase proteins involved in inflammation, such as amyloid P, alpha-1 antichymotrypsin
and C-reactive protein are also plaque components (31) while Immunoglobulin
G is located in the plaque corona (32) . Large increases in IgG levels have
been recorded in the brain parenchyma, in apoptotic dying neurones and in
cerebral blood vessels in the Alzheimer’s disease brain (33) . Complement
component C3 is found in Alzheimer’s disease amyloid plaques along with complement
C4 (34) . Complement components Clq, C3d, and C4d are present in plaques,
dystrophic neurites and neurofibrillary tangles (5) .

The membrane attack complex (MAC), composed of complement
proteins C5 to C9, forms a channel that is inserted into the membranes of
pathogens, destroying them by lysis. These components cannot be detected in
temporal cortex amyloid plaques in Alzheimer’s disease (34;35). However the MAC complex is present in dystrophic neurites
and neurofibrillary tangles (5) and others have detected this complex in neuritic plaques
and tangles, along with deposition of C1q, C3 and clusterin
(36) . The membrane attack complex
has also been detected in the neuronal cytoplasm in AD brains and associated
with neurofibrillary tangles and lysosomes (4).The presence of the MAC complex in neurones might suggest
that neuronal lysis by the MAC complex could contribute to neuronal cell death
(5).

Pathogen seropositivity in Alzheimer’s disease

Increased seropositivity to IgM anti HSV-1 antibodies has been
reported to predict the risk of subsequently developing Alzheimer’s disease
(14) . Increased seropositivity in Alzheimer’s disease has also been reported
for Helicobacter pylori (37) and increased HHV-6 immunoreactivity has been
observed in Alzheimer’s disease CSF samples (38) . No differences in the seropositivity
of Adenovirus, Chlamydia Group B, Coxiella burnettii, Cytomegalovirus, Herpes
simplex virus, Influenza A, Influenza B, Measles and Mycoplasma pneumoniae
were found in a study of 33 Alzheimer’s disease patients and 28 controls (39)
. However, there are a large number of diverse pathogenic antigens with homology
to beta-amyloid, any of which may have been present, potentially provoking
immune response-related neuronal loss, many years prior to seropositivity
testing.

Antibodies and antigenicity

The tenet of the autoimmune hypothesis is that viral and other
pathogens and environmental allergens with homology to beta-amyloid will trigger
the production of antibodies that also target the beta-amyloid peptide. Those
provoking a robust immune, inflammatory and complement response risk killing
beta-amyloid containing neurones. Antibodies to the Potato virus (15) and
to Borrelia antigens (24) ) have already been shown to label amyloid plaques
in the Alzheimer’s disease brain and antibodies to a phage epitope (AEFRH)
also label beta-amyloid (40) .

Potential cross-reactivity can partly be tested in silico
but ultimately requires the characterisation of the autoimmune beta-amyloid
epitopes present in Alzheimer’s disease and cross-reactivity testing between
pathogenic and environmental antigens and beta-amyloid. Thus far, the precise
epitopes labelled by beta-amyloid autoantibodies have not been fully characterised.

The initial rendezvous of antigens with the immune system is
with B-cells which bind to, engulf and digest the antigen. The B-cell epitope
antigenicity prediction (20) for beta-amyloid is illustrated in Figs 2 and
3, over which are laid the pathogens and allergens that match particular sequences
within the beta-amyloid peptide. As can be seen, Coxsackie, HIV-1, HSV-1,
Hepatitis C, influenza, mumps, the respiratory syncitial virus, rhinoviruses
(common cold) and clostridia, enterobacteria and vibrio phages match sequences
that lie within predicted antigenic regions of beta-amyloid (Fig 2). An increase
in immunogenicity is also observed within the VGGVV sequence, which has been
used as an epitope to label beta-amyloid (7) . Allergenic proteins whose sequences
match those of antigenic portions of beta-amyloid include those from fungal,
nut, pollen, insect venom and house dust mites (Table 2, Fig 2).

As a further theoretical test, all consecutive tetrapeptide sequences
within beta-amyloid were screened against the human epitope and the HIV-1
molecular Immunology databases to determine which antigens contain these epitopes.
As shown in Tables 2 to 7 many viral, fungal, bacterial, parasite and allergen
antibodies contain tetrapeptide sequences from the beta-amyloid peptide. In
addition, apart from beta-amyloid isoforms and a small number of mammalian
proteins, the major matching epitopes were concentrated in viral, bacterial,
fungal and allergen classes (i.e. not other species or other mammalian proteins).
These databases contain over 73,000 epitopes, so again the results returned
are highly specific to these classes. This at least shows that antibodies
that have been used to label these viruses, pathogens and allergens, contain
beta-amyloid sequences, and that potential cross-reacting antibodies are concentrated
in these classes.

The ability of autoantibodies to adsorb beta-amyloid can be considered
as useful, and certain of these appear to be associated with reduced plaque
volume (1) . Other autoantibodies, present in normal and Alzheimer’s disease
sera, also possess catalytic properties and are capable of destroying the
toxic peptide. Such antibodies do not form stable immune complexes and are
less likely to activate immune inflammatory and complement related cell lysis
(2) . This is where the danger lies, as antibodies capable of mounting a full-blown
immune response against beta-amyloid are likely to kill the cells in which
the peptide resides. It is relatively common to find Alzheimer’s disease pathology
at autopsy (plaques and tangles) in patients who were cognitively normal shortly
before death (41) . In such patients, it is tempting to suggest that immune-activating
antibodies are rare.

Catalytic beta-amyloid auto-antibodies cleave the beta-amyloid
peptide primarily between the two histidines (H/Q) at Abeta13-14
, and to a lesser extent at other positions as shown in Figs 2 and 3 {Taguchi,
Planque, et al. 2008 1720 /id} . The major cleavage site is within a non-immunogenic
region of the peptide. Interestingly, several plant viruses (Amaranthus, Pepper,
Pistachio, Potato, Rice, Soybean, Sunflower and Zucchini (courgette) and allergens
(Rice, Pistaccio, Soybean as well as the cat allergen and insect venoms)
express proteins homologous to this particular region. Rather intriguingly,
several of these plants/vegetables are constituents of the Mediterranean diet
which has been reported to reduce the risk of developing Alzheimer’s disease
(42) . Such diets impact on cholesterol/lipoprotein function and on atherosclerosis,
a major contributory factor in Alzheimer’s disease (43;44) but could also
conceivably be related to beneficial antibodies generated by the ingestion
of common plant viruses, a possibility that also suggests potential immunisation
strategies.

Certain proteins from three cancer-causing viruses, Epstein-Barr
(HSV-4), Hepatitis B and the human Papillomavirus virus are also homologous
to this catalytic antibody target region, suggesting a plausible explanation
for the inverse association between cancer and Alzheimer’s disease (45)

Vaccinations and Alzheimer’s disease

It has been noted that the risk of developing Alzheimer’s disease
was reduced following vaccination against diphtheria, influenza, polio or
tetanus (46) . Again, sequences within proteins of these pathogens are homologous
to beta-amyloid as shown in Fig 2, (which represents the viral proteins rather
than the epitopes used for vaccination). This is rather encouraging as it
suggests that, if the effect of vaccination is due to beta-amyloid homology,
other vaccines might similarly reduce the incidence of Alzheimer’s disease.
The papillomavirus vaccine, already used to prevent cervical cancer (47) ,
is a prime candidate as a viral protein matches the beta-amyloid region targeted
by catalytic autoantibodies. However, as there is an evident danger of creating
potentially toxic beta-amyloid autoantibodies, characterisation of the epitopes
targeted by such vaccines must be of prime concern.

Epidemiological studies

These observations suggest that Alzheimer’s disease may have
an autoimmune component, triggered by antigenic proteins with homology to
beta-amyloid. Such a scenario helps to explain several, indeed most, epidemiological
features of Alzheimer’s disease. For example, Atopy and autoimmune diseases
are common in Alzheimer’s disease (48;49) , and could relate to allergen
homology with beta-amyloid. Alzheimer’s disease prevalence is higher in women
and in Afro-Americans (50) , as is HSV-2 prevalence (51) .

. Herpes simplex infection is a risk factor in Alzheimer’s disease
acting in synergy with the APOE4 allele (52) and dementia, with Alzheimer’s
disease pathology is common in HIV-1 infected patients (53) , a situation
perhaps explained by viral protein homology with beta-amyloid. Such homology
with pathogen proteins could also explain the association of Borrelia Burgdorferri,
Helicobacter pylori, C.Pneumoniae (23;24) and by inference P.Gingivalis and
Streptococcus mutans (oral pathogens causing periodontitis and tooth loss
(26;27) ) with Alzheimer’s disease. The incidence of Alzheimer’s disease
is also related to the number of pregnancies (54) , which might be explained
by greater exposure to common childhood illnesses (cf phage/bacterial homology
with beta-amyloid). It has also been noted that nuns, who are less exposed
to sexually transmitted pathogens, show some resistance to the ravages of
Alzheimer’s disease (41) . An autoimmune scenario may also explain why the
use of non-steroidal anti-inflammatories reduces the risk of developing Alzheimer’s
disease (55) as do fish consumption and the Mediterranean diet (42;56) .Such
diets are rich in N-3 polyunsaturated fatty acids, which also possess anti-inflammatory
properties (57) . The beneficial effects of these diets and also of statins
(58) are likely to be related to multiple problems in cholesterol and lipoprotein
homoeostasis in Alzheimer’s disease (59) but may also be related to pathogens
and the immune system. For example viral entry is often lipid dependent a
a factor related to fusion of the viral lipid envelope with cell membranes,
and the cellular entry of HIV-1 and herpes simplex is cholesterol and lipid
raft -dependent and blocked by nystatin (60;61) . Statins also habe immunosuppressant
properties (62) . The potential role of viruses as constituents of the Mediterranean
diet has been discussed above in relation to their homology with beta-amyloid
regions targeted by beneficial catalytic autoantibodies. The inverse association
between cancer and Alzheimer’s disease might also be explained in these terms
(see above) and the beneficial effects of vaccination can also be related
to pathogen homology with beta-amyloid (diphtheria, influenza, tetanus and
polio). The risk promoting effects of aluminium in Alzheimer’s disease (63)
might also be explained by its common self-prescribed use as an antacid in
gastrointestinal disturbances (64) often caused by phage/bacterial pathogens
with homology to beta-amyloid.

In short almost all epidemiological observations related to Alzheimer’s
disease can be explained in terms of pathogens and/or autoimmunity.

Late-onset Alzheimer’s disease susceptibility genes

Four genes, Apolipoprotein E, clusterin, complement receptor 1 and PICALM,
are the main suspects in Alzheimer’s disease (65-67) each of which can be
implicated in viral life cycles. For example, APOE binds to HSV-1 (68) and
Hepatitis C viruses (69) and the Alzheimer’s disease risk allele, APOE4, is
also related to HSV-1 and HIV-1 infection, although, curiously, it protects
against Hepatitis C infection (70) . Complement receptor 1 and clusterin
are both involved in the complement cascades that play a crucial role in pathogen
defence (71) . In addition the influenza virus and HSV-1 both bind to complement
receptor 1 on erythrocytes (72) . One of the receptors used by
Herpes simplex for cellular entry is the Mannose-6-phosphate receptor, M6PR
(73). This receptor binds to clusterin (74) and its traffic through the endosomal compartments is controlled
by PICALM, whose overexpression reduces M6PR localisation in endosomes, suggesting
blockade of its transport from the plasma membrane or the trans-golgi network
(75). The Herpes simplex and Influenza viruses also uses exportin
(Crm1) dependent pathways for nuclear egress (76;77). PICALM and other endocytic-regulatory proteins bind to Crm1
(78).

Many minor genes (see www.polygenicpathways.co.uk/alzpolys
for references) are also implicated in viral life cycles. For example lipoprotein
receptors implicated in Alzheimer’s disease (LRP1, LDLR, VLDLR) are used by
human rhinoviruses to gain cellular entry (79) . The nectin receptor PVRL2
is a Herpes viral receptor (80) , as is insulin degrading enzyme (81) . In
addition over 30 immune related genes (chemokines, cytokines, complement related,
toll receptors HLA-antigens) have been implicated as risk factors. All of
these might be expected to modulate immune defence.

Given the plethora of viral and environmental beta-amyloid homologues,
and the presence of autoantibodies to beta-amyloid in healthy aged subjects,
it seems likely that the functional gene variants in the control group, rather
than the Alzheimer’s disease risk promoting genes, may be more important.
These are presumably those that prevent the ravages of autoimmunity.

Familial Alzheimer’s disease

Familial early-onset Alzheimer’s disease is caused by a number
of different mutations in presenilins and the APP gene, including several
mutations as APP717 (V/I, V/M, V/G, V/L) (London mutation and
others) and at KM670/671NL (Swedish mutation) (inter alia :see http://www.molgen.ua.ac.be/ADMutations/)
(82) . These are not within the beta-amyloid sequence. Both mutations modify
APP processing and increase the generation of Abeta 1-42 (83;84)
. In so doing, they may thus be able to increase the probability of Abeta
encountering autoantibodies, both in the brain and in the periphery resulting
in a feed forward further generation of autoantibodies by the immune system.

The APP717 mutant is within two gamma-secretase cleavage
sites generating an undecapeptide as shown in Fig 1. The Swedish mutation
is immediately prior to the beta-secretase cleavage site that, with gamma-secretase,
generates beta-amyloid and frees the native or mutant APP670/671
terminus (85) . Homology searches against viral and bacterial proteomes were
performed using the native and mutant forms of the APP717 undecapeptide and the
nonapaptide upstream of the Swedish mutation sites (Fig 1). The APP717G
mutant increased the predicted B-type immunogenicity of the peptide,
but other mutants were without effect (not shown).

Native APP717 is homologous to several phages, viruses
and bacteria, many of which are common; for example Enterobacteria, lactococcus
and staphylococcus phages, adenovirus, cytomegalovirus, the parainfluenza
virus and rotavirus and the less common rabies and coronaviruses (Table 4).
This native form also shows homology with several bacterial species, which
for the most part, with the exception of Lactobacilli, are pathological rather
than commensal (Table 5).

The various APP717 mutations alter this matching profile
in a number of ways. For example the V/F mutation creates matching peptides
to Herpes viruses HSV-2, 3 and 8 and markedly increases the number of hits
in relation to homology, particularly within bacterial flora (mainly due
do many strains of the commensal E.Faecalis) (Tables 4 and 5).

The APP717 V/G mutant creates a peptide region homologous
to proteins from human herpes virus 6, a pathogen with seroprevalence approaching
100% (86) and to the JC and BK polyomaviruses which also display high seroprevalence
in the normal population ( 39% and 82% respectively (87) ) . This mutant also
creates regions homologous to the endemic soil bacterium B.Cereus, to a bacterium
causing verrucas, and to P.Gingivalis a constituent of the oral flora that
plays a role in periodontitis and tooth loss (tables 4 and 5).

The V/I mutant creates homologues to proteins from over 30 Rhinococcal
strains causing the common cold, to the mumps virus and to the common Norovirus
responsible for vomiting sickness, as well as to the endemic soil bacteria
B.Cereus and S.Aureus, and the commensal E.Coli and P.Gingivalis (Table 4,5).

The V/L mutant creates regions homologous to proteins from Influenza A and
B viruses and to Hepatitis C and Herpes viruses 4 and 5, as well as to the
commensal E.Coli and Streptococcus Hominis (Tabke 4,5).

The native APP670/671 peptide is homologous to a number
of influenza viruses, which are almost exclusively avine. The Swedish mutant
increase the number of viral matches to the upstream peptide, particularly
to enterobacterial phages, and creates homologous regions to several species
of human adenoviruses, which also show high seroprevalence (88) , and to the
respiratory syncitial virus as well as to human rhinoviruses and again to
E.Coli. Several of these mutant peptides are homologous to mycobacterial phages
(see Tables 6,7 ), perhaps explaining why tuberculosis (as well as possession
of the HLA-DR3 allele) have been reported as risk factors in familial
Alzheimer’s disease (49) . The epitopes generated by these mutants are
again concentrated within viral and pathogen proteins, particularly the Vaccinia
Virus (Tables 4-7). There do not appear to have been any studies on autoantibodies
in familial Alzheimer’s disease but the large number of viral and bacterial
peptides perfectly matching the mutant surrounds suggests that autoimmunity
may also play a major role in this disorder. Although clearly genetic, its
pathology may be autoimmune related, as well as to, or perhaps rather than
aberrant beta-amyloid processing.

In short, these mutants, in different ways, all increase the
number and variety of viral and bacterial matches, to commensal (Particularly
E.Coli, E.Faecalis and P.Gingivalis ) as well as to pathological species (Clostridia,
Mycobacteria, Vibrio, inter alia) and create homologous regions to
very common pathogens causing the common cold, influenza, herpes infections
and periodontitis.

APP transgenic mice

If autoimmunity rather than problems in APP processing is relevant,
this could explain why APP transgenic models do not faithfully mimic Alzheimer’s
disease (i.e. extensive cholinergic neuronal loss, loss of hippocampal afferents
and efferents and massive cortical degeneration) (89) . There have been two
studies assessing the effects of infection in APP transgenic mice. Repeated
Streptococcus Pneumoniae infection had no effect on pathology or behaviour
in APP Tg2576 transgenic mice (Swedish mutant) (90) . S.Pneumoniae displays
homology to both the native and mutant forms of the relevant peptide (Table).
Borna virus infection resulted in a reduction in beta-amyloid immunoreactivity
in the brains of infected Tg2576 transgenic mice (91) . This virus also displays
homology to both the native and mutant forms of the peptide (Table). S.Pneumoniae
also expresses proteins containing the VGGVV sequence, as do a large number
of other bacteria (not shown), while a homology search for Borna virus proteins
containing VGGVV yielded no hits. However, in relation to autoimmunity, it
is not the infection itself, but the antibodies generated in response to the
infection that could cause the problem. A more suitable test might be repeated
challenge with specific antigens in APP transgenic models.

Other models capable of producing cerebral beta-amyloid deposition
in mice include C.Pneumoniae (92) or HSV-1 infection (11) , the latter also
producing hippocampal and entorhinal cortex neuronal loss and memory deficits,
perhaps more faithfully reproducing the pathology of Alzheimer’s disease
(13) . Such models may be useful in APP transgenic mice.

Beta-amyloid and other Vaccines and therapies.

.

The F,G and I APP717 mutants all generate peptides
homologous to the related Vaccinia and Variola (Smallpox) viruses (Table 4,6)
. While vaccination against diphtheria, flu, tetanus and polio have been reported
to reduce the risk of late-onset Alzheimer’s disease (see above) there is
also a possibility of vaccine cross-reactivity with endogenous peptides such
as beta-amyloid. Many of the epitopes formed by these mutant peptides are
contained within Vaccinia viral proteins. There is thus a possibility that
smallpox vaccination may be a contributory factor in familial Alzheimer’s
disease, although this requires characterisation of the epitopes present in
the vaccine, which was generated from the virus rather than from peptide components.
The vaccinia virus has also been used as a primary vaccination against smallpox
(93) following on from Edward Jenner’s pioneering experiments with cowpox
over 200 years ago (94) . This is a contentious area, but the possibility
that vaccination might trigger nefarious autoantibody generation does need
to be addressed, particularly in future studies.

The potential use of beta-amyloid antibodies is based on their
ability to reduce plaque burden and neurite dystrophy in APP transgenic mice
(95)

Several studies have demonstrated that beta-amyloid antibodies reduce plaque
burden in APP transgenic models and that they can also improve cognitive performance
(96) . However amyloid antibodies extracted from the serum of old APP transgenic
mice potentiate the toxicity of beta-amyloid and Alzheimer’s disease patients
display an enhanced immune response to the peptide (97) . Again in transgenic
mice, different immune backgrounds can influence the type of immune responses
elicited by beta-amyloid. For example B-and T-cell responses to beta-amyloid
can be modified in HLA-DR3,
-DR4,

-DQ6 or -DQ8 transgenic mice (98)
. HLA-antigen diversity in Man is also likely to determine the outcome of
beta-amyloid/antibody interactions.

The results of this survey suggest that beta-amyloid autoantibodies
might cause as well as mitigate against Alzheimer’s disease pathology. Beta-amyloid
vaccination in Alzheimer’s disease (against Abeta1-42) has so far
not been successful and sadly resulted in meningoencephalitis and the death
of a patient (99) . While certain beta-amyloid antibodies may reduce plaque
burden, there is an evident risk that they may also trigger an auto-immune
response, potentially killing beta-amyloid containing neurones. Catalytic
autoantibodies are less able to form stable immune complexes and likely represent
the safest way forward in this area (2) . It is intriguing that the beta-amyloid
region targeted by catalytic autoantibodies matches peptide sequences of viruses
that are constituents of the Mediterranean diet and of cancer-inducing viruses
(Epstein-Barr, Hepatitis B, and the papillomavirus) as both cancer and the
Mediterranean diet are inversely associated with Alzheimer’s disease risk
(see above). Vaccines to the human papillomavirus already exist (47) and could
perhaps be considered as a therapeutic or preventive option in Alzheimer’s
disease, after due consideration of the epitope matches.

If beta-amyloid autoantibodies are the culprits, techniques such
as immunoadsorption, which has proved to be of benefit in Myasthenia gravis
(autoimmunity to acetylcholine receptors (100) or immunosuppressant use might
be considered as potential therapeutic options. There is indirect evidence
in support of such treatment. Natural immunoadsorbants include silica, which
is however toxic, (101) , tryptophan and phenylalanine (102) . Levels of silica
in drinking water are inversely related to Alzheimer’s disease risk (103)
and serum tryptophan levels are markedly depleted in Alzheimer’s disease patients,
a marker of immune activation (104) .Phenylalanine plasma levels are in contrast
increased in Alzheimer’s disease (105) . Fish oil (see above) also suppresses
T-Lymphocyte activation (106) and statins, which have also been reported to
reduce Alzheimer’s disease risk (58) are also immunosuppressant (62) .

Heterogeneity in genetic and epidemiological studies

If there is one factor common to polygenic disorder research
it is the discordance of genetic and environmental association data in this
and other diseases. However, if, as suggested by this survey, there are dozens
of potential Alzheimer’s disease triggers, all funnelling towards a common
cause, this heterogeneity becomes part of the answer and not part of the problem.
Different gene products are related not only to human physiology, but also
to pathogen life cycles (e.g. rhinoviruses and lipoprotein receptors, APOE
and Herpes Simplex or influenza and complement receptor 1) , a situation that
has been discussed in relation to Alzheimer’s disease and Schizophrenia susceptibility
genes and pathogens implicated in these disorders (107;108) . Viruses and
bacteria are not uniformly distributed worldwide, nor is antibody seroprevalence,
and different environmental risk factors may similarly vary from region to
region. The heterogeneity observed in these studies thus has a rational basis,
reflecting the heterogeneity of cause, and need not necessarily be considered
as a statistical artefact

Relevance to other autoimmune and genetic diseases and evolutionary aspects

.

A homology search against viral proteomes with known autoantigens
from multiple sclerosis, myaesthenia gravis, pemphigus vulgaris, systemic
lupus erythematosus, and Chronic obstructive pulmonary disease retuned viral
matches, which in all cases were relevant to the viruses implicated as risk
factors in each disease (Table 8) , also identifying other suspects. Furthermore,
in other genetic disorders, Huntingtons’s disease and
other polyglutamine repeat disorders (Dentatorubropallidoluysian atrophy,
Kennedy disease and Spinocerebellar ataxias (109;110) ) and Cystic fibrosis,
the mutations created homologues with several viral or phage proteins. The
QQQ polyglutamine triplet is a B-cell epitope according to the BEpiPred server
and each successive QQQ addition increases the overall antigenicity of the
resulting peptide (not shown). As an example of a risk promoting gene in polygenic
disorders, APOE4 also aligns with several relevant viral proteins. Given the
capacity of the immune system to generate vast repertoires of antibodies,
some of these pathogens will no doubt generate antibodies that also target
important human proteins implicated in autoimmune and genetic diseases. The
genetic mutations often create physiological problems related to their normal
function and the effects of the mutation, but the overall effect of the mutation,
particularly in relation to autoimmune-related degeneration, may be compounded
by these viral matches.

Phages and viruses are the simplest form of “life”, as defined
by the possession of DNA/RNA and a proteinaceous structure, and were long
ago proposed as the origin of higher cellular organisms (111;112) . There
are currently 2463 viral genomes in the NCBI database, probably representing
but a small proportion of those existing on the planet. While perhaps responsible
for our origin these predecessors may have donated a legacy of human viral-derived
proteins that closely match antigenic proteins in the currently existing virome
that could be responsible for many human diseases including genetic disorders,
autoimmune disorders, polygenic diseases, and those that have so far baffled
research, such as ME (Myalgic encephalomyelitis/chronic fatigue syndrome) and fibromyalgia.
This evidently has enormous implications for therapy and prevention, not only
of autoimmune disorders, but also of polygenic and human genetic disorders,
until now generally regarded as unassailable. Vaccination, using epitopes
against the non homologous human protein regions of the phages and viruses
could perhaps destroy the pathogen and prevent the associated problems related
to autoimmunity.

Summary and conclusions

Many common viruses, phages, bacteria, fungi, parasites and allergens
express proteins with marked homology to antigenic and other regions of the
beta-amyloid peptide. Epitope similarity with beta-amyloid is concentrated
within these classes and it seems likely that these antigens provide a source
of the beta-amyloid autoantibodies found in the ageing population and in Alzheimer’s
disease. While some of these antibodies may be benevolent, others may stimulate
immune, inflammatory and other defensive measures, including complement mediated
cell lysis that could kill the neurones in which the peptide resides. Activation
of the immune system is supported by the presence of many immune-related proteins
in Alzheimer’s disease amyloid plaques, and by the presence of the complement
membrane attack complex in Alzheimer’s disease neurones. Reduced serum tryptophan
levels, and an increased immune response to beta-amyloid also suggest immune
activation. Familial Alzheimer’s disease may also have a strong autoimmune
component, as the various APP mutants convert the surrounding peptides to
matches to commensal bacteria (E.Coli, E.Faecalis and P.Gingivalis) and to
viruses with a high seroprevalence (HHV-6, polyoma viruses, influenza and
the common cold rhinoviruses). The categorisation of Alzheimer’s disease as
an autoimmune disorder explains most of the epidemiological observations in
Alzheimer’s disease and the major genes implicated in Alzheimer’s disease
are all related to viral life cycles and/or to the complement arm of the immune
defence network.

Diseases caused by these viruses, fungi or the bacteria infected
with the phage/beta-amyloid homologues are very common and often recurrent
(e.g. colds, influenza gastroenteritis or food poisoning) as is exposure to
certain allergens (e.g. dust mites , cat, cow, horse allergens, pollen and
food allergens, insect stings, marine algae etc) Over time, and with increasing
age, the major risk factor in Alzheimer’s disease (113) , antibodies that
may also target beta-amyloid are more likely to be produced, gradually increasing
the probability of a self-immune attack on neurones containing the beta-amyloid
peptide. There may thus be dozens, if not hundreds of triggers promoting Alzheimer’s
disease risk, all funnelling towards an autoimmune scenario. If this is the
case, then Alzheimer’s disease might be considered as an autoimmune disorder
and immunosuppressants or antibody adsorption might have a role to play in
its therapy, once diagnosed. C.Neoformans eradication can result in a complete
recovery, in very rare cases of diagnosed dementia (28;29) , and Helicobacter
elimination has been reported to ameliorate cognitive function in infected
Alzheimer’s disease patients (25) . Aggressive targeting of opportunistic
pathogens capable of mimicking the beta-amyloid peptide might thus be considered
as a therapeutic option. Because so many are homologous to beta-amyloid, such
therapy might well have to be tailored to individual pathogens, depending
on the species identified by serum assay.

Vaccination against common diseases has already been shown to
reduce the risk of developing Alzheimer’s disease (46) and, in the long term,
vaccination against other common viruses and bacteria might also be of benefit,
although it is evident that potential vaccine antibody cross-reactivity with
beta-amyloid must be a prime concern. One such vaccine may already exist in
the form of that for the human papillomavirus.

. In summary, the close homology of diverse viral, fungal bacterial
and allergenic antigens with beta-amyloid and to peptides generated by APP
mutations suggests an autoimmune component to familial and late-onset Alzheimer’s
disease, triggered by these antigenic homologues. The autoimmune scenario
explains many epidemiological observations and genetic studies also implicate
the immune system and viral life-cycles. If autoimmunity is important, vaccination,
viral and pathogen elimination and immunosuppressant therapy might be expected
to play a role in the prevention and therapy of Alzheimer’s disease and perhaps
provide new rationales for developing a cure. This type of viral matching
is also relevant to other autoimmune and genetic disorders and may be a near
universal phenomenon reflecting our viral ancestral roots. This generality
could open new therapeutic avenues in many human diseases.

Acknowledgements: Thanks to the numerous authors for reprints, to Oliver
Chao and Nasire Mahmudi for finding others, and to Maria Jesus Martin at Uniprot
and Tao Tao at NCBI for help with the mysteries of BLAST and Clustal alignment
settings.

Table 1: Virus and phage proteins containing the VGGVV sequence, and the
diseases they cause. Accession numbers are provided and seroprevalence is
recorded for human viruses where available.

Virus

Protein VVGGV

Disease

Seroprevalencs

Human Viruses

Dengue virus 1

ACQ44424

Polyprotein

Febrile tropical disease

Endemic in some countries (eg
100% seroprevalence in Jamaica)
(114)

Hepatitis C

ACY65348
envelope protein 2 :

ADG28960 NS4A

ABC58527

NS4B: ADC54771

Polyprotein

Hepatitis

An estimated 270-300 million
people worldwide are infected with hepatitis C

No data on these strains but
for other polyoma viruses can range from 9 to 69% (87)

Yellow fever virus

NP_776003

Polyprotein : NS2A

Yellow Fever

75% Nigeria
(118)

Phages
infecting human bacteria and diseases associated with the bacteria

Aeromonas phage

YP_238875

WAC

Gastroenteritis and
wound infections

Enterobacteria phage

NP_037676

tail length tape measure protein

Normal gut flora,
many of which can cause gastrointestinal problems

Escherichia
phage

Chain
A, Ibv: YP_002003548

hypothetical protein

Many are harmless
but can cause diarrhoea to dysentery

Mycobacterium Phage

ACU41726

GP233

YP_002014682

GP71 YP_655916

YP_655355 GP51 GP78

NP_818073

GP108

Pulmonary disease,
Tuberculosis and leprosy

Prochlorococcus phage

ACY76180

Hypothetical protein

Marine cyanobacteria

Pseudomonas phage

Tail fiber assembly
protein

Nosocomial hospital
infections

Serratia
phage KSP20

TAILC_BPSK2

Nosocomial hospital
infections

Streptomyces phage

NP_958289

ORF9

Antibiotic producing
bacteria

Vibrio phage

AAQ96489

Hypothetical protein

Gastroenteritis, septicaemia

Other phages

Azospirillum
phage

YP_001686888

Hypothetical protein

Nitrogen fixing plant
bacterium

Halomonas phage

YP_001686782

hypothetical protein HAPgp46

Salt water

Microcystis
aeruginosa phage

YP_851126

hypothetical protein MaLMM01_gp112

Harmful blue-green
algae

Prochlorococcus
phage

ACY76180

hypothetical protein PSSM2_305

Common marine cyanobacteria

Synechococcus
phage

YP_003097380

tailfiber like protein

hypothetical protein SRSM4_083

Marine cyanobacteria

Agricultural Viruses

Bovine
herpesvirus 5

YP_003662471
Envelope glycoprotein K

Cattle

Bovine
herpesvirus type 2

P12641
Envelope glycoprotein B

Cattle

Bovine
viral diarrhea virus

CAD67689
hypothetical protein

Cattle

Avian
infectious bronchitis virus

ACJ12832
polyprotein 1ab

Poultry

Infectious bronchitis
virus

Replicase
polyprotein 1ab: , Ibv Nsp3 Adrp Domain

Poultry

Equid herpesvirus 1,
4 and 9

YP_002333504

NP_045240

YP_053068

tegument protein UL37

Horse

Suid herpesvirus 1

YP_068340.Tegument
protein UL37

Pigs

Swinepox virus

NP_570175 kelch-like
protein

Pigs

Plant,
food and environmental viruses

Anguillid herpesvirus
1

YP_003358210

ORF71

Eel

Viral hemorrhagic
septicemia virus

ADB93794 Polymerase:
Large protein

Fish

Cherry necrotic rusty
mottle mosaic virus

ABZ89196Replication
protein

Cherry

Radish mosaic virus

BAG84603 Polyprotein

Radish

Watermelon mosaic
virus

ACF60797 Polyprotein

Watermelon

Ostreid herpesvirus
1

YP_024568ORF23

Oyster

Arabis mosaic virus

BAF35852 Polyprotein:
NTB binding domain

Strawberries and raspberries

Viral hemorrhagic septicemia
virus

ADB93794Polymerase;
Large protein

Fish

Shrimp white spot
syndrome virus

NP_477731 wsv209

Shrimp

Antheraea pernyi nucleopolyhedrovirus

ABQ12330 ETM

Environment Insect

Chinese Tuss Moth

Murid herpesvirus
2

NP_064139 pR34

Environment Rodents

Allpahuayo virus

NP_064139 Nucleocapsid
protein

Environment Rodents

Helicobasidium
mompa endornavirus 1

YP_003280846
Polyprotein

Environment Root rot
fungus

Paramecium
bursaria Chlorella virus

YP_001498106 and others
Hypothetical proteins

Environmental Algae

Archaeal
BJ1 virus

YP_919057 hypothetical
protein BJ1_gp30

Environmental

West
Caucasian bat virus

YP_919057. Glycoprotein
G

Environmental Bat

Cyprinid herpesvirus
3

BAF48875

ORF62

Family pet Goldfish

Caviid herpesvirus
2

BAF48875

GP144

Family pet Guinea
Pig

Macropodid herpesvirus
1

AAD11961 Glycoprotein
B

Zoo Marsupial

Macropodid herpesvirus
2

AAD11960.

Glycoprotein B

Zoo Marsupial

Macacine
herpesvirus 1

NP_851887 Glycoprotein
B

Zoo Monkey

Cercopithecine herpesvirus
1, 2 and 16

BAC58067 eg

Envelope glycoprotein B

Zoo Monkey

Papiine herpesvirus 2

AAA85650

Envelope glycoprotein B

Zoo Monkey

Chimpanzee
alpha-1 herpesvirus

BAE47051 Glycoprotein
B

Zoo Monkey

Allergens

Lichwort
:Parietaria officinalis

AAB36010

major allergen {N-terminal, band 2}

Non-stinging nettle
family growing on rubbish and walls

Table 2:

Viral and allergen proteins matching tetrapeptide sequences, or more, within
the beta-amyloid peptide (1-42). Shaded dark grey blocks represent viral
matches to pentapeptides, or more, as shown by the numbers in each block.
Allergens are boxed in light grey and protein accession numbers are provided.
Species with protein epitopes containing these sequences are also illustrated.
Short beta-amyloid epitopes (antibodies raised to peptides of 4-6 amino acids)
are illustrated by the grey boxes with dashed surrounds. Matches to these
short immunogenic peptides are perhaps more likely to cross-react with beta-amyloid.

Table 3: Beta-amyloid homologous regions for proteins from Borrelia Burgdorferri,
Chlamydia Pneumoniae, Helicobacter pylori, Porphyromonas Gingivalis and Streptococcus
Mutans. Protein accession numbers are provided and proteins with matches to
pentapeptides or more are boxed in grey. The number of matching amino acids
is shown in each box.

Table 4: The
effects of the APP717 mutations (in Red) on homology to viral proteins.
Protein accession numbers are provided and amino acid matches are indicated
by the asterisks or by the red letter of the mutant amino acid. Species with
proteins containing epitopes matching those of the peptide amino acids are
also shown (Marked by E). Phages infecting commensal bacteria and common viruses
(eg Rhinoviruses and influenza) are highlighted in bold.

Table 5 The effects of the APP717 mutations on homology to bacterial
proteins. Protein accession numbers are provided and amino acid matches are
indicated by the asterisks or by the red letter of the mutant amino acid.
Commensal or common soil species are highlighted in bold.

Native 180 protein Hits

I

A

T

V

I

V

I

T

L

V

Ricketsia canadensis A8EYN4

*

*

*

*

*

V

*

*

Aliivibrio salmonicida B6EPV1

Bacillus coagulans C1PC89

Rhodococcus Q0S6X2

Vibrio Metshnikovii C9P7P7

*

*

*

*

*

V

*

Chlorobium ferrooxidans Q0YSY2

Hoeflea phototrophica A9CXL6

Rickettsia canadensis A8EYN4 (Plants)

Silicibacter pomeroyi Q5LMG7

*

*

*

*

V

*

*

Ralstonia Eutropha Q472E0 (infects plants)

Ralstonia Picketii C6BIS4

Ralstonia solanasereum B5SKC7

Staphylococcus warneri C4W9N9

*

*

*

V

*

*

*

*

Acinetobacter baumannii A3M8V0

bacterium Ellin514 B9XI38

Carboxydibrachium pacificum B7RAI3

Clostridium asparagiforme C0CUU7

Erwinia tasmaniensis B2VL62

Lactobacillus Brevis Q03NB9

Lactobacillus crispatus D4FF71

Oxalobacter formigenes C3XCI5

Ralstonia solanacereum Q8XYV2:

Ryzobium

Salmonella enterica B5QA19

Salmonella heidelberg B5P6H1

Salmonella typhimurium A9N7S6

Thermoanaerobacter brockii C5UE75

Thermoanaerobacter congensis Q8R7X3

Thermoanaerobacter ethanolicus C7IUT0

Thermoanaerobacter pseudethanolicus B0KCL9

Thermoanaerobacter mathranii C6Q925

Vibrio fischeri B5EV74

*

*

*

V

*

*

*

Carboxydibrachium pacificum

Clostridium asparagiforme C0CUU7

Clostridium bartlettii B0A6Z5

Clostridium thermocellum A3DFT3

Geobacillus sp. D3EBU3

Halothermothrix oreni B8CZE2

Maricaulis maris Q0AK61

Oligotropha carboxidovorans :B6J9Z4

Ralstonia pickettii B2UHX3

Sinorhizobium medicae A6U9B8

Tsukamurella paurometabola C2AKX9

Yersiniarohdei C4UTM6

Yersiniamollaretii C4SBZ5

*

*

V

*

*

*

*

Mutant F 859 protein hits

I

A

T

V

I

F

I

T

L

V

Aerococcus viridans D4YI11

Brachyspira hyodysenteriae C0QX46

Brevibacillus brevis C0ZA23

Clostridium butyric C4IJA0

Clostridium thermocellum D1NR57

Lactobacillus helveticus C9M4P6

Lactobacillus sakei Q38YE0

Oceanicola granulosus Q2CH54

Rhodobacterales bacterium A3VMF7

Vibrio fischerii B5FCH7

*

*

*

*

*

F

*

Chloroherpetonia thalassium B3QTP3

Enterococcus faecalis Q838I9 (many strains)

Bacteroides vulgatus D4V0E1

*

*

*

*

F

*

*

Vibrio Fischerii Q5E6H3

*

*

*

*

*

F

*

Blautia Hansenii C9L542

Jannaschia sp Q28MI1

Providencia rettgeri D4BTW4

Providencia rustigianii D1NYV5

Rhodobacter sphaeroides Q3IZP4

Yersiniaintermedia C4T272

*

*

*

F

*

*

*

Enterobacter cloacae D5CJ25

Idiomarina loihiensis Q5QU47

Proteus mirabilis C2LG18

Proteus penneri C0B3I7

Providencia alcalifaciens B6XHS9

Providencia stuartii B2Q1T7

Vibrio Furnissii C9PCZ1

*

*

F

*

*

*

*

Mutant G 433 protein Hits

I

A

T

V

I

G

I

T

L

V

Psychrobacter arcticus Q4FTU9

*

*

*

*

*

G

*

*

*

Psychrobacter arcticus Q4FTU9

Streptosporangium roseum D2AZ15

*

*

*

*

G

*

*

*

Azorhizobium caulinodans A8HZ46

Bacillus mycoides C3AFH5

Catonella Morbia C4FVR1

Desulfuromonas acetoxidans Q1K1U7

Desulfovibrio Sp D2L952

Desulfovibrio magneticus C4XPD3

Dialister invisus C9LN97

Fusobacterium Varium C6JJE4

Granulibacter bethesdensis Q0BPF8

Hydrogenivirga sp A8V376

Legionella longbeachae D3HQH8

Leuconostoc citreum B1MYU7

Marinobacter aquaeolei A1U1N5

marine gamma proteobacterium A0Z7W7

Methylophaga thiooxidans C0N9Z9

Microcystis aeruginosa B0JM06

Nitrosomonas europaea Q82TG1

Photorhabdus asymbiotica C7BLV9

Vibrio alginolyticus D0X1F5

Vibrio harveyi A7MSV9

Yersinia pseudotuberculosis B7UF92

*

*

*

*

*

G

*

Alcanivorax borkumensis Q0VS59

Bacillus cereus C2Y6K4 (Endemic soil)

Bacillus selenitireducens A8VSL6

Bacillus thuringiensis :C3IF91

Bacillus thuringiensis serovar israelensis Q3EPC6

Colwellia psychrerythraea Q482L7

Cyanothece sp. B1WRV0

Desulfococcus oleovorans Y1531

Dickeya dadantii D2BW75

Grimontia hollisae D0I6P8

Marine algicola DG893

Marinobacter aquaeolei A1U1P8

Natranaerobius thermophilus B2A0H4

Photobacterium angustum Q1ZQS6

Photobacterium profundum Q1Z1I8

Prevotella timonensis D1W1B7

Tolumonas auensis C4LCT3

*

*

*

*

G

*

*

Bacillus licheniformis D2AZ15

Blastopirellula MarinaA3ZUC0

Brevibacillus Brevis C0Z7B6

Clostridium phytofermentans A9KJY1

Porphyromonas gingivalis Q7MVP9

Stenotrophomonas maltophilia B4SHS1

Verrucomicrobiae Bacterium B5JCZ1

*

*

*

G

*

*

*

Acidovorax avenae D1STI2

Acidovorax ebreus B9MID3

Aeromonas hydrophila subsp. A0KHV9

Anaeromyxobacter sp. A7HEH4

Azorhizobium caulinodans A8IHP8

Azospirillum sp :D3P7H8

Bradyrhizobium sp A5EP47

Clostridium bolteae A8S3D7

Clostridium perfringens Q8XMX7

Dichelobacter nodosus A5EXF8

Gemellahaemolysans C5NVY9

Legionella longbeachae D3HN24

Leifsonia xyli Q6AED0

Methylibium petroleiphilum A2SD15

Methylobacterium extorquens C7C7Z2

Methylococcus capsulatus Q608X6

Mycoplasma penetrans Q8EUZ6

Myxococcus xanthus Q1DG48

Nakamurella multipartita C8X6U6

Pantoea ananatis :D4GKU3

Photobacterium profundum Q6LPG3

Polaromonas naphthalenivorans A1VT83

Ralstonia solanacearum A3RYP0

Rhodopseudomonas palustris Q6N682

leguminosarum bv. Trifolii C6AXC8

Rhizobium etli B3PP68

Rhizobium leguminosarum bv. Viciae Q1MBB9

Rhizobium meliloti Q92T03

Salinispora arenicola A8M7N9

Shewanella putrefaciens A2V1T8

Sinorhizobium medicae A6UEY9

Stenotrophomonas sp. B8KYQ9

Stenotrophomonas maltophilia B4SHS1

Syntrophobacter fumaroxidans A0LQ89

Thermosynechococcus elongatus Q8DHF1

Thermosipho melanesiensis A6LLD4

Thermotoga maritima Q9WYD7

*

*

G

*

*

*

*

Mutant I 158 Protein Hits

I

A

T

V

I

I

I

T

L

V

Citrobacter
oseri A8AEH8

Citrobacter rodentium D2TQJ9

Clostridium phytofermentansA9KJW1

Desulfobacterium autotrophicum C0QE66

Enterobacter sp A4WC96

Escherichia coli Q8FG29 (many
strains)

Escherichia ferguson B7LUH8

Parachlamydia acanthamoebae D1R803

Shigella boydii Q323G5

Shigella dysenteriae B3WWP7

Shigella flexneri Q83R02

Veillonella dispar C4FS24

Yersinia intermedia C4T4Q3

*

*

*

*

*

I

*

Bacillus cereus A7GLY6

Clostridium Humboltae A8RT62

Escherichia coli Q8X7P3

Grimontia hollisae D0I556

Haemophilus parasuis B8F464

Porphyromonas gingivalis B2RJP3

Staphylococcus aureus Q99RA3 Many strains

Xenorhabdus bovienii D3UZ08

*

*

*

*

*

I

Lactobacillus brevis Q03NB9

Lactobacillus iners C8PC46

Vibrio metschnikovii C9P8Z2

*

*

*

*

I

*

*

*

Clostridium perfringens Q8XLI1

Leptospira biflexa B0SNI9

Pedobacter heparinus C6Y2P1

Sphingobacterium spiritivorum C5PSB0

*

*

*

*

I

*

*

Erwinia amylovora D4HU72

Erwinia pyrifoliae D2TBW3

Listeria innocua

Phytoplasma australiense B1V943

*

*

*

I

*

*

*

Bacteroides sp D0TSW3

Bacteroides ovatus A7M5Q2_

Borrelia garinii B7XSM5

Clostridium difficile Q186M9

Clostridium cellulolyticum :B8I278

Corynebacterium urealyticum B1VG78

Pasteurella dagmatis C9PSK3

Proteus mirabilis C2LEY0_

Streptobacillus moniliformis D1AXI5

*

*

I

*

*

*

*

Mutant L 198 Protein Hits

I

A

T

V

I

L

I

T

L

V

Acidobactium Q1IJL1

Aggregatibacter actinomycetemcomitans D4ED73

Aggregati bacteria aphrophilus C6AKL6

Abiotrophia defectiva C4G6M0

Azorhizobium Caulinodans A8HQR6

Bacillus megaterium D5DSJ5

Bacillus pumilus B4ADS6

Bdellovibrio bacteriovorus Q6MRD1

Caulobacter crescentus B8H097

Clostridiales bacterium C5EIM1

Clostridium butyricum C4ICE7

Clostridium methylpentosum C0ECW3

Chlamydophila abortus Q5L6C5

Coprococcus Comes C0BFC3

Doreaformici generans B0G8H5

Eikenella Corrodens C0DY03

Mycobacterium sp Q1BC56

Roseobacterium denitrificans Q162L0

Ruminococcus obeum D4LS87

*

*

*

*

*

L

*

Carnobacterium sp A8UAH5

Mycobacterium abscessus B1MP36

Mycobacterium chelonae A5A9P9

*

*

*

L

*

*

*

*

Bacilluscereus lus Rock3-44 C3AYE2

Bacillus thuringiensis Q3EUN8_

*

*

*

*

L

*

*

*

Bacillus mycoides C3AYE2

Bacillus pseudomycoides C3BEV6

Gramella forsetii A0LYP6

Lyngbya sp A0YPN4

Lysinibacillus sphaericus B1HWG7

*

*

*

L

*

*

*

Butyrate-producing bacterium D4MSZ1

Citreicella Sp. D0D4G6

Clostridium sp. D4CDQ6

Escherichia coli B5AXC7

Leifsonia xyli subsp.xyli Q6AFD7

Mycoplasma Pulmonis MYPU_0850

Neptuniibacter caesariensis :Q2BPQ0

Rhodopseudomonas palustris Q21C19_

Ruminococcus torques A5KJD0

Staphylococcus hominis C2LWL2

Veillonella dispar C4FNF7

Veillonella parvula D1BQP4

Yersiniarohdei C4UUS1

Yersinia frederiksenii C4SLT3

*

*

L

*

*

*

*

Table
6 The effects of the Swedish
APP mutation on homology to viral proteins. Protein accession numbers are
provided and amino acid matches are indicated by the asterisks or by the
red letter of the mutant amino acid. Species with proteins containing epitopes
matching those of the peptde amino acids are also shown (Marked by E) Phages
infecting commensal bacteria and common viruses (eg Rhinoviruses and influenza)
are highlighted in bold.

Table 7 The effects of the Swedish
mutations on homology to bacterial proteins. Protein accession numbers are
provided and amino acid matches are indicated by the asterisks or by the
red letter of the mutant amino acid. Commensal or common soil bacteria are
highlighted in bold.

Bacteria

T

E

E

I

S

E

V

K

M

Atopobium
Parvilum C8WAI5

*

*

*

*

*

*

*

*

Bermanella
maris Q1N288

Shewanella violacea

D4ZM52

*

*

*

*

*

*

*

Vibrio
furnissii C9PJ26

*

*

*

*

*

*

*

Lactis subsp Q031F7

Lactocococcus cremoris

A2RIQ5 Same
for both

*

*

*

*

*

*

Bacillus anthracis C3PD86

Bacillus thuringiensis C3HJR4

Bacillus thuringiensis serovar pondicheriensis C3GK36

Baciillus Cereus C2THS7 several strains

*

*

*

*

*

*

*

Clostridum
tetani Q896K9

Oceanobacillus Q8CV16

*

*

*

*

*

*

*

Colwellia psychrerythraea Q487K7

Enterococcus Faecium D3LK32

Ricketsia Typhi Q68XP3

Rickettsia Prowazekii O05942

Photorabdus luminens Q7N0P2 Same for both

*

*

*

*

*

*

*

Streptobacillus
moniliformis

D1AV81

*

*

*

*

*

*

*

Leptotrichia Buccalis

C7NE35
Rumibococcus Sp C6JEQ4
Streptococcus pneumoniae

ABJ55426

Sams for both

*

*

*

*

*

Clostridium beijerinckii A6LY25 Sanme for both

*

*

*

*

*

*

*

Planctomyces maris A6C251

*

*

*

*

*

*

Leptospira
biflexa B0SKY9 Sane for both

*

*

*

*

*

Mycoplasma
hominisD1J7S2

*

*

*

*

*

*

Sodalis glossinidius Q4LC19 Same for both

*

*

*

*

*

*

Nodularia
spumigena A0ZE12 Same for both

*

*

*

*

*

Streptococcus
pneumoniae ZP_01821444 Same for both

*

*

*

*

*

T

E

E

I

S

E

V

N

L

Fusobacterium sp C3WJ64

*

*

*

*

*

N

L

Fusobacterium mortiferum C3WDH2

*

*

*

*

*

N

L

Acidobacterium psulatum C1F5P2

*

*

*

*

*

*

N

L

Corynebacterium matruchotii C5VDU4

Escherichia coli O1 57 H7 Q8X597

Escherichia coli O6 Q8FGX7

Escherichia coli (strain UTI89 / UPEC) Q1RB23

Escherichia coli O6 Q0TH59 and numerous other E.Coli
strains

Shigella flexneriQ83RH3 Helicobacter
hepaticus Q7VIZ4

Staphylococcus haemolyticus Q4L6V6

Trichodesmium erythraeum Q10V04

*

*

*

*

*

*

N

Bacteroides thetaiota Q8A9X8

Anaerococcus lactolyticus C2BI02

*

*

*

*

*

N

L

Synechococcus sp. Q7U980

*

*

*

*

*

*

-

L

Listeria grayi C2BZ78

Streptococcus pneumoniae ZP_01817518

*

*

*

*

N

L

Citrobacter Youngae D4B9G4

Pseudoalteromonas atlantica Q15N87

Pseudomonas
chlororaphis P31521

Pseudomonas fluorescens C3K287

Rhodobacter sphaeroides A4WVX1

Robiginitalea biformata A4CHQ4

Streptococcus pneumoniae CAI34213

*

*

*

N

L

Streptococcus pneumoniae ZP_02717209

*

*

*

*

N

Table 8

Viral proteins lining up with autoantigens from Chronic obstructive pulmonary
disease, myasthenia gravis, multiple sclerosis and pemphigus vulgaris and
to mutant proteins from polyglutamine repeat disorders (Huntington’s disease,
Dentatorubropallidoluysian atrophy, Kennedy disease and Spinocerebellar ataxias)
and from cystic fibrosis. APOE4 is included as an example of a risk factor
in a number of polygenic diseases. Accession numbers and the aligning sequences
are shown with references where the virus has been implicated in the relevant
disease. The polyglutamine expansions also increase the antigenicity of the
resultant peptide with each triplet QQQ addition.

Viral protein matches to different regions of the beta-amyloid peptide in
relation to the predicted B Cell Epitope antigenicity. Predicted epitopes
are marked with an asterisk and the Y-axis is an index of antigenicity. The
VGGVV epitope has been used to label beta-amyloid and is marked + as are other
short epitopes used to label beta-amyloid (QKLV, FFAE, IIGL) Other short epitopes
used to label beta-amyloid include MGGVV, VGGVV, MVGGVV, VGGVV and GGVVIA).
The viruses and bacteria in black boxes represent those where vaccination
was reported to reduce the incidence of Alzheimer’s disease. These alignments
are to viral proteins rather than to epitopes within the vaccine. The arrows
represent the beta-amyloid cleavage sites of the catalytic beta-amyloid autoantibodies
isolated from Alzheimer’s disease sera. H*↑Q is the major site of catalysis.
Note that cancer and plant viruses overlap this region. Burk= Burkholderia
Phage; CampPhage = Campylobacer
Phage; HumRespSyn = Human respiratory syncitial Virus; HepC = Hepatitis C;
HIV = Human Immunodeficiency Virus; HSV-1 = Herpes simplex (Human Herpesvirus
1); Mycobact = Mycobacteria phage; Strep = Streptococcus phage; C.Tet = Clostridium
Tetani, C.Dip = Corynebacterium diphtheriae (See Table 2 for Accession numbers)

Figure 3

Allergenic protein matches to different regions of the beta-amyloid peptide
in relation to the predicted B Cell Epitope antigenicity. Predicted epitopes
are marked with an asterisk and the Y-axis is an index of antigenicity .Allergens
expressing proteins that match different regions of the beta-amyloid peptide
are aligned with their respective matches. The arrows represent the beta-amyloid
cleavage sites of the catalytic beta-amyloid autoantibodies isolated from
Alzheimer’s disease sera. H*↑Q is the major site of catalysis (see Table
2 for Accession numbers).